• alternation between mild-moderate deppresion and hypomania
• commonly progress to bipolar 1

• classic bipolar I- full manic episodes alternating with major depression 
• bipolar II- hypomania alternating with major depression

• onset usually in adolescence
• can present initially as unipolar (treatment with ADD's can switch into mania)
• equal risk for men and women
• highly recurrent
• causes unknown
• comorbidities common (anxiety disorders, drugs/alcohol dependence)

The key is sedation

• antipsychotics (haloperidol, olanzapine)
• IV benzodiazepines (diazepam, lorazepam, clonazepam)
• anticonvulsants (sodium valproate, lamotrigine)
• lithium (NOT have much effect ACUTELY)

• lithium carbonate (treat both "poles")
• mood stabilizers
  • anticonvulsants (sodium valproate, lamotrigine)
  • atypical antipsychotics (olanzapine)

• usually tx bipolar disorders with antidepressants, but may cause significant problems:
  • can cause switch from depression to hypomania or mania
  • higher risk with TCA, SNRI (NE component)
  • could increase rapidity and depth of cycling
• initial presentation of depressive episode could be either MDD or bipolar disorder
  • it is believed young people that committed suicide that are treated with ADD's are actually bipolar
  • crucial to monitor response of patients, esp. with first few wekks of initial episode
  • family history of bipolar helpful
• lithium can be helpful in managing depression as an adjunct of ADD

• drug of choice for maintenance of bipolar disorder
  • lower response in more severe forms of disease
  • gradual response
• you can start it in acute manic emergencies, lithium can be started
  • acute calming effects are generally insufficient given alone
• MDD (adjunct to antidepressants)
• schizoaffective disorder (adjucnt to antipsychotics)

low TI, but mainly adverse effects with chronic use. OD common with normal therapy often due to changes in renal clearance

• tremor (common)
  • tx with beta blockers
• sedation, fatigue
• GI problems: diarrhea, nausea
• edema (increase aldosterone)
• mild hypothyroidism (reversible, non progressive)
• skin problems: acne, psoriasis
• renal
  • neprhon inflammation (very little loss of function detectable)
  • loss of ADH effectiveness = nephrogenic diabetes insipidus
    • tx with thiazide diuretics, amiloride
  • polydypsia, polyuria- avoid dehydration

• toxicity
  • confusion
  • ataxia
  • hypotension
  • arrhythmias
  • convulsions
  • coma
• tx- supportive, dialysis w/osmotic diuretics

• absorbed well orally (complete in 8 hrs)
• distributed to total body water
• excreted in urine uncahnged
  • 80% filtered is reabsorbed
    • clearance lower in elderly
    • altering this can alter blood levels
• kinetics
  • peak plasma levels 2-4 hrs
  • half life 20-24 hrs
• since low TI, must do significant blood level monitoring

• start with low dose for 5 days to achieve steady state
• 10-12 hrs after dose measure blood levels
• based on clinical response, can adjust dose
• typical effective blood levels (0.6-1.0 mEq/L)
• slow release preps useful to minimize toxic peaks
  • absorption more variable
  • this may increase GI toxicity

• increased sodium eecretion causes decreased lithium excretion and this leads to increased lithium levels causing toxicity
  • caution/dosage reduction: sodium depleting diuretics
    • thiazide diuretics
    • loop diuretics
  • dehydration
  • NSAIDS
  • ACE inhibitors
• increased lithium excretion will decrease its blood levels
  • mannitol
  • acetazolamide (CA inh.)
  • theophyline

• benzodiazepines- clonazepam most common
  • indications
    • acute manic episodes
    • anxiety associated with bipolar disorders
• anticonvulsants (other than BZ's)
  • indications
    • acute manic episodes
    • adjunct with lithium for maintenance
    • monotherapy for maintenance
    • becoming first line for treating bipolar II
• atypical antipsychotics (same indications as anticonvulsants)

Mechanism unclear

• quicker responses
• we can increase dose faster
• more useful in emergencies
• safer (higher TI)
• better tolerated in many patients (adverse effects usually less)
• efficacy may be lower in severe disease, hospitalized patients
  • some who dont respond to lithium may respond to one of these drugs
  • lamotrigine appears better for depressive episodes
• drugs of choice for bipolar II and cyclothymia

• valproic acid
• lamotrigine (significant antidepressant activity and usually used in combo with lithium)
  • lamotrigine presents depressive episodes while lithium prevents manic episodes

• nausea
• dizziness
• headache
• rash

• GI distress
• weight gain
• alopecia

• olanzapine
• indications
  • equivalent to lithium for bipolar I
  • sedation properties allow it to be good for manic emergencies
• adverse effects: weight gain, DM risk

• not all drugs increase amines are good ADD's
• blocking amine receptors doesn't cause depression
• blockade occurs acutely and remision takes weeks

• brain derived neurotrophic factor (BDNF) levels drop in depression and are increased by ADD's
• in studies, BDNF infusion had ADD like effects
• BDNF can regulate dendritic sprouting and also cause neurogenesis esp. in hippocampus
  • ADD's shown to enhance hippocampal neurogenesis
  • hippocampus important for CNS role in HPA axis
  • depression with decreased hippocampal volume

• associated with increased stress
  • most MDD patients dont show dexamethasone suppression (ie: dysregulation of HPA axis)
  • severity of depression correlates with increase HPA dysreg
  • exogenous glucocorticoids associated with mood and cognitive symptoms similar to MDD
• thyroid disorder- 25% of MDD patients have abnormal thyroid function
• sex steroids
  • estrogen deficiency contribute to MDD in many women
    • likewise severe testosterone def. in men
  • HRT leads to improved mood
  • menstrual cycling can be strongly related to mood responsiveness